If the inflammatory response to inhalation of cigarette smoke causes chronic obstructive pulmonary disease (COPD), suppression of that natural response might be beneficial. We hypothesized that a smoker's risk of developing COPD is inversely related to physiologic levels of two fatty acids that have antiinflammatory properties: eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6). The proportion of each fatty acid in plasma lipids was measured in 2,349 current or former smokers. COPD was identified and defined by clinical symptoms and/or spirometry. After adjustment for smoking exposure and other possible confounders, the prevalence odds of COPD were inversely related to the DHA (but not to the EPA) content of plasma lipid components in most of the models. For example, as compared with the first quartile of the DHA distribution, the prevalence odds ratios (ORs) for chronic bronchitis were 0.98, 0.88, and 0.69 for the second, third, and fourth quartiles, respectively (p for linear trend = 0.09). The corresponding ORs for COPD as defined spirometrically, were 0.65, 0.51, and 0.48 (p < 0. 001). Among 543 current heavy smokers, adjusted mean values of FEV1 (lowest to highest DHA quartile) were 2,706, 2,785, 2,801, and 2,854 ml. DHA may have a role in preventing or treating COPD and other chronic inflammatory conditions of the lung. Pilot testing of that hypothesis in experimental models seems warranted.